This is a revised application to renew a project focused on genetic and epidemiologic approaches to understanding the etiology and course of bipolar disorder (BP). The main goal is to identify one or more genes for BP using standard linkage analysis as well as linkage disequilibrium (LD) mapping, a complementary approach. Such analyses have already been used to localize a gene responsible for susceptibility to severe BP in the chromosome 18q23 region, based on whole genome genetic mapping studies that were performed as part of a companion project. The proposed studies will facilitate fine genetic mapping and positional cloning studies to identify this gene. As in the current award, the study population, in Costa Rica, consists of affected individuals and their relatives. Many subjects will still be drawn from extended pedigrees and several newly identified informative families will be included in the study. In addition, for the purpose of conducting LD mapping a substantial number of individuals will be sampled from hospitals and clinics. Genealogical reconstruction will play a crucial role in the study and diagnostic evaluations will continue to represent the bulk of the workload in this project. Genome screening studies have highlighted several genome regions that may contain BP susceptibility loci (in addition to the 18q23 locus). The sample to be collected in the next award period will be used to increase the information obtainable in each of these regions. More refined mapping and positional cloning will require addition to both the family (linkage) and individual (LD) samples. Obtaining diagnostic information on several hundred individuals, has generated a substantial clinical database. Analysis of these data will be used to obtain more complete characterization of BP phenotypes and to evaluate factors that conceivably interact with genes to determine the severity and course of BP, such as drug and alcohol use.